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Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model

View Article: PubMed Central - PubMed

ABSTRACT

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars.

No MeSH data available.


Related in: MedlinePlus

Efficacy of NB-DNJ and MON-DNJ in guinea pigs challenged with EBOV.Female guinea pigs were infected with 103 pfu of EBOV (Zaire strain) via IV cannula then treated by the same route TID (between 9am and 5pm) with 1850 mg/kg/day NB-DNJ (n = 4), 120 mg/kg/day MON-DNJ (n = 4) or placebo (n = 4) for 14 days. (A) Percentage of surviving animals. (B) Signs of illness. (C) Body temperature, compared to their temperature on day 0 (baseline) and (D) weight change as a percentage of body weight on day 0 (baseline). Mean for remaining animals in each group plotted for B, C and D. Asterisks indicate significantly different weights (p < 0.05; Mann-Whitney test) between animals in placebo and NB-DNJ-treated groups at day 3 (p = 0.0304) and in NB-DNJ- and MON-DNJ-treated groups at day 4 (p = 0.0304) and day 5 (p = 0.0304).
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pone.0167018.g002: Efficacy of NB-DNJ and MON-DNJ in guinea pigs challenged with EBOV.Female guinea pigs were infected with 103 pfu of EBOV (Zaire strain) via IV cannula then treated by the same route TID (between 9am and 5pm) with 1850 mg/kg/day NB-DNJ (n = 4), 120 mg/kg/day MON-DNJ (n = 4) or placebo (n = 4) for 14 days. (A) Percentage of surviving animals. (B) Signs of illness. (C) Body temperature, compared to their temperature on day 0 (baseline) and (D) weight change as a percentage of body weight on day 0 (baseline). Mean for remaining animals in each group plotted for B, C and D. Asterisks indicate significantly different weights (p < 0.05; Mann-Whitney test) between animals in placebo and NB-DNJ-treated groups at day 3 (p = 0.0304) and in NB-DNJ- and MON-DNJ-treated groups at day 4 (p = 0.0304) and day 5 (p = 0.0304).

Mentions: The first efficacy study dosed animals on day 0 immediately following EBOV challenge, TID with doses equally spread within an ~8 hour period (~ 9:00, 13:00 and 17:00) with 1850 mg/kg/day NB-DNJ (n = 4), 120 mg/kg/day MON-DNJ (n = 4) or water placebo (n = 4). Survival analysis showed all animals meeting humane endpoints at days 9–11 post-challenge except for an animal in the NB-DNJ treated group which survived until the end of the study (Fig 2A). Animals from all groups began to show clinical signs from day 4 post challenge with those in the placebo and MON-DNJ groups increasing in severity and all animals in these groups were euthanised on day 9–10 post challenge (Fig 2B). Animals treated with NB-DNJ showed reduced signs of illness on days 7–8, compared with placebo and MON-DNJ treated animals, even though all animals in the study had elevated temperatures (Fig 2C) indicative of EBOV infection. The reduced weight gain observed in NB-DNJ-treated animals in the toxicity study (Fig 1), was also observed in this challenge study (Fig 2D). The weight loss of 1 animal in the NB-DNJ group plateaued on days 8–10, then reversed (Fig 2D); this animal had no fever or clinical signs left on day 14 and survived the critical phase of disease (Fig 2A).


Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model
Efficacy of NB-DNJ and MON-DNJ in guinea pigs challenged with EBOV.Female guinea pigs were infected with 103 pfu of EBOV (Zaire strain) via IV cannula then treated by the same route TID (between 9am and 5pm) with 1850 mg/kg/day NB-DNJ (n = 4), 120 mg/kg/day MON-DNJ (n = 4) or placebo (n = 4) for 14 days. (A) Percentage of surviving animals. (B) Signs of illness. (C) Body temperature, compared to their temperature on day 0 (baseline) and (D) weight change as a percentage of body weight on day 0 (baseline). Mean for remaining animals in each group plotted for B, C and D. Asterisks indicate significantly different weights (p < 0.05; Mann-Whitney test) between animals in placebo and NB-DNJ-treated groups at day 3 (p = 0.0304) and in NB-DNJ- and MON-DNJ-treated groups at day 4 (p = 0.0304) and day 5 (p = 0.0304).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120828&req=5

pone.0167018.g002: Efficacy of NB-DNJ and MON-DNJ in guinea pigs challenged with EBOV.Female guinea pigs were infected with 103 pfu of EBOV (Zaire strain) via IV cannula then treated by the same route TID (between 9am and 5pm) with 1850 mg/kg/day NB-DNJ (n = 4), 120 mg/kg/day MON-DNJ (n = 4) or placebo (n = 4) for 14 days. (A) Percentage of surviving animals. (B) Signs of illness. (C) Body temperature, compared to their temperature on day 0 (baseline) and (D) weight change as a percentage of body weight on day 0 (baseline). Mean for remaining animals in each group plotted for B, C and D. Asterisks indicate significantly different weights (p < 0.05; Mann-Whitney test) between animals in placebo and NB-DNJ-treated groups at day 3 (p = 0.0304) and in NB-DNJ- and MON-DNJ-treated groups at day 4 (p = 0.0304) and day 5 (p = 0.0304).
Mentions: The first efficacy study dosed animals on day 0 immediately following EBOV challenge, TID with doses equally spread within an ~8 hour period (~ 9:00, 13:00 and 17:00) with 1850 mg/kg/day NB-DNJ (n = 4), 120 mg/kg/day MON-DNJ (n = 4) or water placebo (n = 4). Survival analysis showed all animals meeting humane endpoints at days 9–11 post-challenge except for an animal in the NB-DNJ treated group which survived until the end of the study (Fig 2A). Animals from all groups began to show clinical signs from day 4 post challenge with those in the placebo and MON-DNJ groups increasing in severity and all animals in these groups were euthanised on day 9–10 post challenge (Fig 2B). Animals treated with NB-DNJ showed reduced signs of illness on days 7–8, compared with placebo and MON-DNJ treated animals, even though all animals in the study had elevated temperatures (Fig 2C) indicative of EBOV infection. The reduced weight gain observed in NB-DNJ-treated animals in the toxicity study (Fig 1), was also observed in this challenge study (Fig 2D). The weight loss of 1 animal in the NB-DNJ group plateaued on days 8–10, then reversed (Fig 2D); this animal had no fever or clinical signs left on day 14 and survived the critical phase of disease (Fig 2A).

View Article: PubMed Central - PubMed

ABSTRACT

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars.

No MeSH data available.


Related in: MedlinePlus